title: A combined molecular modeling study on a series of pyrazole/isoxazole based human Hsp90α inhibitors.
abstract: Inhibition of the protein chaperone Hsp90α is a promising approach for cancer therapy. In this work, a molecular modeling study combining pharmacophore model, molecular docking and three-dimensional quantitative structure-activity relationships (3D-QSAR) was performed to investigate a series of pyrazole/isoxazole scaffold inhibitors of human Hsp90α. The pharmacophore model can provide the essential features required for the biological activities of the inhibitors. The molecular docking study can give insight into the binding mode between Hsp90α and its inhibitors. 3D-QSAR based on CoMFA and CoMSIA models were performed from three different strategies for conformational selection and alignment. The receptor-based models gave the most statistically significant results with cross-validated q                         (2) values of 0.782 and 0.829 and r                         (2) values of 0.909 and 0.968, for CoMFA and CoMSIA respectively. Furthermore, the 3D contour maps superimposed within the binding site of Hsp90α could help to understand the pivotal interaction and the structural requirements for potent Hsp90α inhibitors. The results show 4-position of pyrazole/isoxazole ring requires bulky and hydrophobic groups, and bulky and electron repulsion substituent of 5-amides is favorable for enhancing activity. This study will be helpful for the rational design of new potent Hsp90α inhibitors.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Huanxiang
authors.initials: H
authors.lastname: Liu
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Jin
authors.initials: J
authors.lastname: Qin
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yao
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; D007555:Isoxazoles; D011720:Pyrazoles